ES2613098T3 - Fluorinated bisphenol ether compounds and methods for use - Google Patents

Abstract

A compound having a structure of Formula I: ** Formula ** or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: R1 is F, OH or OY; R2, R3 R5, R6, R7 and R9 are each independently H or F; R4 is H, F, OH or OY; R8 is OH or OY; R10 and R11 are each independently F or C1-C5 alkyl; and Y is a moiety selected from: ** Formula ** in which (aa) is any naturally occurring amino acid side chain and n is an integer between 1-200; where at least one of R1, R2, R3, R4 or R5 is F.

Description

Fluorinated bisphenol ether compounds and methods for use

Background

Technical field

This invention relates to therapeutic products, their uses and compounds for use in methods for the treatment of various indications, including various cancers. In particular, the invention relates to compounds for use in therapies and treatment methods for cancers, such as prostate cancer, including all stages and androgen-dependent, androgen-sensitive and castration-resistant cancers (also referred to as castration). as hormone refractory, androgen independent, resistant to androgen deprivation, resistant to androgen ablation, independent of androgen depletion, recurring from castration, recurring with anti-androgens).

Description of the related technique

Androgens mediate their effects through the androgen receptor (AR). Androgens play a role in a wide range of developmental and physiological responses and are involved in male sexual differentiation, maintenance of spermatogenesis and regulation of male gonadotropin (R. K. Ross, G.

A. Coetzee, C. L. Pearce, J. K. Reichardt, P. Bretsky, L. N. Kolonel, B. E. Henderson, E. Lander, D. Altshuler & G. Daley, Eur Urol 35, 355-361 (1999); A. A. Thomson, Reproduction 121, 187-195 (2001); N. Tanji, K. Aoki & M. Yokoyama, Arch Androl 47, 1-7 (2001)). Several lines of evidence show that androgens are associated with the development of prostate carcinogenesis. First, androgens induce prostate carcinogenesis in rodent models (RL Noble, Cancer Res 37, 1929-1933 (1977); RL Noble, Oncology 34, 138-141 (1977)) and men who receive androgens in shape of anabolic steroids have a higher incidence of prostate cancer (JT Roberts & DM Essenhigh Lancet 2, 742 (1986); JA Jackson, J. Waxman & AM Spiekerman, Arch Intern Med 149, 2365-2366 (1989); PD Guinan, W. Sadoughi, H. Alsheik, RJ Ablin, D. Alrenga & IM Bush, Am J Surg 131, 599-600 (1976)). Second, prostate cancer does not develop if humans or dogs are neutered before puberty (JD Wilson & C. Roehrborn, J Clin Endocrinol Metab 84, 4324-4331 (1999); G. Wilding, Cancer Surv 14, 113-130 (1992)). Castration of adult males causes involution of the prostate and apoptosis of the prostate epithelium while producing no effect on other male external genitalia (E.

M. Bruckheimer & N. Kyprianou, Cell Tissue Res 301, 153-162 (2000); J. T. Isaacs, Prostate 5, 545-557 (1984)). This dependence on androgens provides the underlying reason for treating prostate cancer with chemical or surgical castration (androgen ablation).

Androgens also play a role in female cancers. An example is ovarian cancer, in which elevated androgen levels are associated with an increased risk of developing ovarian cancer (KJ Helzlsouer, AJ Alberg, GB Gordon, C. Longcope, TL Bush, SC Hoffman & GW Comstock, JAMA 274, 1926-1930 (1995); R.

J. Edmondson, J. M. Monaghan & B. R. Davies, Br J Cancer 86, 879-885 (2002)).)). RA has been detected in most ovarian cancers (HA Risch, JNatl Cancer Inst 90, 1774-1786 (1998); BR Rao & BJ Slotman, Endocr Rev 12, 14-26 (1991); GM Clinton & W. Hua, Crit Rev Oncol Hematol 25, 1-9 (1997)), while the estrogen-alpha receptor (ERa) and the progesterone receptor are detected in less than 50% of ovarian tumors.

The only effective treatment available for advanced prostate cancer is the removal of androgens, which are essential for the survival of prostate epithelial cells. Androgen ablation therapy causes a temporary reduction in concomitant tumor burden with a decrease in serum-specific prostate antigen (PSA). Unfortunately, prostate cancer can grow back in the absence of testicular androgens (castration-resistant disease) (Huber et al 1987 Scand J. Urol Nephrol. 104, 33-39). Castration-resistant prostate cancer is biochemically characterized before the onset of symptoms by an increasing titer of serum PSA (Miller et al 1992 J. Urol. 147, 956-961). Once the disease becomes resistant to castration, most patients succumb to their disease within two years.

The AR has distinct functional domains that include the carboxy-terminal ligand binding domain (LBD), a DNA binding domain (DBD) comprising two zinc finger motifs and an N-terminal domain (NTD) containing one or more transcriptional activation domains. The binding of the androgen (ligand) to the LBD of the AR causes its activation so that the receptor can effectively bind to its specific DNA consensus site, called the androgen response element (ARE), in the promoter and enhancer regions of genes "normally" regulated by androgens, such as PSA, to initiate transcription. RA can be activated in the absence of androgens by stimulation of the cAMP-dependent protein kinase (PKA) pathway, with interleukin-6 (IL-6) and by various growth factors (Culig et al 1994 Cancer Res. 54, 5474 -5478; Nazareth et al 1996 J. Biol. Chem. 271, 19900-19907; Sadar 1999 J. Biol. Chem. 274, 7777-7783; Ueda et al 2002 A J. Biol. Chem. 277, 7076-7085; and Ueda et al 2002 B J. Biol. Chem. 277, 38087-38094). It has been shown that the mechanism

Independent transformation of the AR ligand involves: 1) an increase in nuclear AR protein that suggests a nuclear translocation; 2) an increase in the formation of AR / ARE complexes; and 3) AR-NTD (Sadar 1999 J. Biol. Chem. 274, 7777-7783; Ueda et al 2002 A J. Biol. Chem. 277, 7076-7085; and Ueda et al 2002 B J. Biol. Chem 277, 38087-38094). RA can be activated in the absence of testicular androgens by alternative signal transduction pathways in castration-resistant disease, which is consistent with the finding that nuclear AR protein is present in secondary tumors of prostate cancer (Kim et al 2002 Am. J. Pathol. 160, 219-226; and van der Kwast et al 1991 Inter. J, Cancer 48, 189-193).

Available AR inhibitors include nonsteroidal antiandrogens such as bicalutamide (Casodex ™), nilutamide, flutamide, MDV3100 and RNA-509 research drugs, and steroidal antiandrogen, cyproterone acetate. These antiandrogens target the ARB of the AR and fail predominantly due to the low affinity and mutations that lead to the activation of the AR by these same antiandrogens (Taplin, ME, Bubley, GJ, Kom YJ, Small EJ, Uptonm M., Rajeshkumarm B., Balkm SP, CancerRes., 59, 2511-2515 (1999)). These antiandrogens will also have no effect on newly discovered RA splicing variants that lack the ligand binding domain (LBD) to result in a constitutively active receptor that promotes the progression of androgen independent prostate cancer (Dehm SM , Schmidt LJ, Heemers HV, Vessella RL, Tindall DJ., Cancer Res 68, 5469-77, 2008; Guo Z, Yang X, Sun F, Jiang R, Linn DE, Chen H, Chen H, Kong X, Melamed J , Tepper CG, Kung HJ, Brodie AM, Edwards J, Qiu Y., Cancer Res. 69, 2305-13, 2009; Hu et al 2009 Cancer Res. 69, 16-22; Sun et al 2010 J Clin Invest. 2010 120, 2715-30).

Conventional therapy has focused on the androgen-dependent activation of AR through its C-terminal domain. Recent studies that develop AR antagonists have focused on the C-terminal and specifically: 1) the allosteric pocket and AF-2 activity (Estebanez-Perpina et al 2007, PNAS 104, 1607416079); 2) in silico "repositioning of drugs" procedure for the identification of non-steroidal antagonists (Bisson et al 2007, PNAS 104, 11927-11932); and coactivator or co-repressor interactions (Chang et al 2005, Mol Endocrinology 19, 2478-2490; Hur et al 2004, PLoS Biol 2, E274; Estébanez-Perpiña et al 2005, JBC 280, 8060-8068; He et al 2004, Mol Cell 16, 425-438).

AR-NTD is also a target for drug development (for example, WO 2000/001813), since NTD contains Activation Function-1 (AF-1) which is the essential region required for transcriptional activity. AR (Jenster et al 1991, Mol Endocrinol. 5, 1396-404). AR-NTD plays an important role in the activation of RA in the absence of androgens (Sadar, MD 1999 J. Biol. Chem. 274, 7777-7783; Sadar MD et al 1999 Endocr Relat Cancer. 6, 487-502; Ueda et al 2002 J. Biol. Chem. 277, 7076-7085; Ueda 2002 J. Biol. Chem. 277, 3808738094; Blaszczyk et al 2004 Clin Cancer Res. 10, 1860-9; Dehm et al 2006 J Biol Chem. 28 , 27882-93; Gregory et al 2004 J Biol Chem. 279, 7119-30). AR-NTD is important in the hormonal progression of prostate cancer as shown by the application of decoy molecules (Quayle et al 2007, Proc Natl Acad Sci USA. 104,13311336).

Although the crystalline structure has been resolved for the C-terminal AR LBD, this has not been the case for the NTD due to its high flexibility and intrinsic disorder in solution (Reid et al., 2002, J. Biol. Chem. 277 , 20079-20086), thus hindering the approaches of discovery of virtual coupling drugs.

Recent advances in the development of compounds that modulate AR include bis-phenol compounds disclosed in PCT published WO 2010/000066 of British Columbia Cancer Agency Branch and The University of British Columbia. Although such compounds look promising, there is still a need in the art for additional and / or improved compounds that modulate the AR, and that provide treatment for the conditions that benefit from such modulation.

Brief Summary

The invention is defined by the appended claims.

The compounds described herein can be used for in vivo or in vitro (ie, non-clinical) research uses to investigate the mechanisms of orphan and nuclear receptors (including steroid receptors such as the androgen receptor). In addition, these compounds can be used individually or as part of a kit for in vivo or in vitro research to investigate signal transduction pathways and / or activation of orphan and nuclear receptors using recombinant proteins, cells maintained in culture, and / or animal models

This invention is also based in part on the surprising discovery that the compounds described herein can also be used to modulate AR activity both in vivo and in vitro for both research and therapeutic uses. In particular, the experiments performed in support of the present invention show that the presence of a chlorine residue and at least one fluorine residue in the disclosed compounds imparts an unexpectedly improved activity compared to other known AR modulators (see for example, Examples 5-9). The compounds can be used in an effective amount so that the activity of the androgen receptor can be modulated. The AR can be mammalian, for example, human. In

In particular, the compounds can be used to inhibit AR. The modulating activity of the compounds can be used both in an in vivo model and in an in vitro model for the study of at least one of the following indications: prostate cancer, breast cancer, ovarian cancer, salivary gland carcinoma, Endometrial cancer, hair loss, acne, hirsutism, ovarian cysts, polycystic ovarian disease, early puberty 5 (testoxicosis), spinobulbar muscular atrophy (SBMA, Kennedy disease), and age-related macular degeneration. In addition, the modulating activity of the compounds can be used for the treatment of at least one of the following indications: prostate cancer, breast cancer, ovarian cancer, endometrial cancer, salivary gland carcinoma, hair loss, acne, hirsutism ovarian cysts, polycystic ovarian disease, precocious puberty, spinobulbar muscular atrophy, and macular degeneration related to

10 age The indication for treatment may be prostate cancer. Prostate cancer can be a castration-resistant prostate cancer. Prostate cancer can be androgen dependent prostate cancer. In other examples, the indication is Kennedy disease.

In accordance with one embodiment, a compound having a structure of Formula I: 15 is provided

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10 and R11 are as defined by the appended claims, and in which at least one of R1, R2, R3, R4 or R5 is F.

In other embodiments, the present disclosure provides the use of a compound of Formula I, to modulate the activity of the androgen receptor (AR). Methods for modulating the AR are also provided, as well as pharmaceutical compositions comprising a compound of Formula I and a pharmaceutically acceptable excipient.

In addition, the present disclosure provides combination therapy treatments for any of the pathologies disclosed herein, for example prostate cancer. The disclosed therapies include the use of a pharmaceutical composition comprising a compound of Formula I, an additional therapeutic agent and a pharmaceutically acceptable excipient. Methods and compositions are also provided.

30 related to them.

These and other aspects of the invention will be apparent by reference to the following detailed description. For this purpose, various references are set forth herein that describe in more detail certain background information, procedures, compounds and / or compositions.

Brief description of the drawings

Figures that do not belong to the invention are for illustrative purposes only.

40 In the figures, identical reference numbers identify similar elements. The relative sizes and positions of the elements in the figures are not necessarily drawn to scale, and some of these elements are enlarged and arbitrarily positioned to improve the readability of the figure. In addition, the particular forms of the elements as they have been drawn are not intended to convey any information regarding the actual form of the particular elements, and have been selected solely to facilitate recognition in the figures.

Figures 1A and 1B represent the inhibition of androgen-dependent proliferation by a representative compound of the invention and a comparative compound. Figure 2 shows the inhibition of transactivation of the N-terminal androgen receptor domain by a representative compound of the invention and a comparative compound.

50 Figure 3 presents data showing tumor regression. Figure 4 represents the change in tumor volume for each mouse. Figure 5 is a graph showing the change in body weight after treatment with representative compounds of the invention and a comparative compound. Figure 6 shows the tumor volume as a function of time after the first injection with compounds

55 comparatives Figure 7 presents the tumor volume data. Figure 8 shows the change in tumor volume for each mouse treated with the comparative compounds.

Figure 9 presents the data of the change in body weight for mice treated with comparative compounds.

Detailed description

The invention is defined by the appended claims.

I. Definitions

In the following description, certain specific details are set forth to provide a complete understanding of

10 different embodiments. However, one skilled in the art will understand that the invention can be practiced without these details. In other cases, known structures have not been shown or described in detail to avoid unnecessarily complicating the descriptions of the embodiments. Unless the context requires otherwise, throughout the specification and the claims that follow, the word "understand" and variations thereof, such as "comprises" and "comprising", should be interpreted in a open and inclusive sense is

15 say, such as "including, but not limited to." In addition, the headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

The reference throughout this specification to "an embodiment" or "an embodiment" means that a particular function, structure or feature described in relation to the embodiment is included in at least one embodiment. 20 Therefore, the occurrences of the expression "in one embodiment" in various places throughout this specification do not necessarily all refer to the same embodiment. In addition, the particular functions, structures, characteristics can be combined in any suitable manner in one or more embodiments. In addition, as used herein and in the appended claims, the singular forms "a", "a" and "the" include plural references unless the content clearly dictates otherwise. Must also

It should be noted that the term "or" is generally used in its sense including "and / or" unless the content clearly indicates otherwise.

The expressions below, as used herein, have the following meanings, unless otherwise indicated:

"Alkyl" refers to a straight or branched chain hydrocarbon radical that is saturated having one to twelve carbon atoms, and which is attached to the rest of the molecule by a single bond. Alkyls comprising any number of carbon atoms from 1 to 12 are included. An alkyl comprising up to 5 carbon atoms is a C1-C5 alkyl. A C1-C5 alkyl includes C5 alkyls, C4 alkyls, C3 alkyls, C2 alkyls and alkyl

C1 (ie, methyl).

Non-limiting examples of saturated C1-C5 alkyl include methyl, ethyl, n-propyl, i-propyl, sec-propyl, n-butyl, ibutyl, sec-butyl, t-butyl and n-pentyl. Non-limiting examples of C2-C5 alkenyl include vinyl, allyl, isopropenyl, 1-propene-2-yl, 1-butene-l-yl, 1-butene-2-yl, 1-butene-3-yl, 2- butene-1-yl, 2-butene-2-yl, pentenoyl and the like.

Non-limiting examples of C2-C5 alkynyl include ethynyl, propynyl, butynyl, pentinyl and the like.

"Hydroxy" or "hydroxyl" refers to the radical -OH.

"Fluorine" and "chlorine" refer to fluorine (F) and chlorine (Cl) substituents, respectively, and also include radioisotopes thereof.

As used herein, the symbol "

"(hereinafter referred to as" a junction bond point ") represents a bond that is a junction point between two chemical entities, one of which is represented as attached to the junction bond point and the other of which is not represented as attached to the junction binding point. For example, "

"is not represented as attached to the binding junction point. For example," XY "indicates that the chemical entity" XY "is linked to another entity through the binding binding point. In addition, the specific binding point to the chemical entity not represented can be specified by inference, for example, the compound CH3-R3, in which R3 is Ho

60 "

"infers that when R3 is" XY ", the junction link point is the same link as the link" infers that when R3 is "XY", the junction link point is the same link as the link through which R3 It is represented as attached to CH3.

II. Compounds and methods

As indicated above, the present disclosure provides a compound having a structure of Formula I:

or a pharmaceutically acceptable salt or stereoisomer thereof, in which:

R1 is F, OH or OY;

R2, R3 R5, R6, R7 and R9 are each independently H or F; R4 is H, F, OH or OY; R8 is OH or OY; R10 and R11 are each independently F or C1-C5 alkyl, and Y is a remainder of Table I;

20 in which at least one of R1, R2, R3, R4 or R5 is F.

In another embodiment, the compound has one of the following structures (Ia), (Ib), (Ic) or (Id):

In some embodiments of any of the above embodiments, R1 is F, and in other embodiments R1 is OH. 30 In still other embodiments, at least one of R1, R4 or R8 is OY.

In some other embodiments of any of the above embodiments, each of R6 and R7 is H.

In some other embodiments of any of the above embodiments, R8 is OH, and in some other embodiments, R9 is H. In certain embodiments, R8 is OH and R9 is H.

In still other embodiments of any of the above embodiments, each of R4 and R5 is H. In other embodiments, R4 is F, and in other embodiments R4 is OH. In still other embodiments, at least two of R1, R2, R3, R4

and R5 are F. In some embodiments, at least three of R1, R2, R3, R4 and R5 are F. Even in other embodiments, at least four of R1, R2, R3, R4 and R5 are F, and in other embodiments , each of R1, R2, R3, R4 and R5 is F.

In some embodiments of any of the above embodiments, at least one of R10 or R11 is F, for example, in some embodiments, each of R10 and R11 is F. In some other embodiments, at least one of R10 or R11 is methyl, for For example, in some embodiments, each of R10 and R11 is methyl.

In certain embodiments of any of the above embodiments, Y is

or

In still other embodiments, the compound of Formula (I) has one of the following structures:

or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, the compound of formula I has the following structure (1):

or a pharmaceutically acceptable salt or stereoisomer thereof.

In other embodiments, the compound of formula 1 has the following structure (1a):

or a pharmaceutically acceptable salt thereof. In still other embodiments, the compound of formula 1 has the following structure (1b):

or a pharmaceutically acceptable salt thereof. In still other embodiments, the compound of formula 1 has the following structure (1c):

or a pharmaceutically acceptable salt thereof. In some additional embodiments, the compound of formula 1 has the following structure (1d):

or a pharmaceutically acceptable salt thereof. Each R10 can independently be C1-C5 alkyl. Every R10

it can be independently C1-C4 alkyl. Each R10 can independently be C1-C3 alkyl. Each R10 25 can independently be C1-C2 alkyl. Each R10 can be independently methyl. Each R10 can be

R10 R10

independently C2 alkyl. Each can be independently C3 alkyl. Each can be

R10 R10

independently C4 alkyl. Each can be independently C5 alkyl. Each can be independently F.

Each R11 can independently be C1-C5 alkyl. Each R11 can independently be C1-C4 alkyl. Every

R11

it can be independently C1-C3 alkyl. Each R11 can independently be C1-C2 alkyl. Each R11 can be independently methyl. Each R11 can independently be C2 alkyl. Each R11 can be

R11 R11

independently C3 alkyl. Each can be independently C4 alkyl. Each can be independently C5 alkyl. Each R11 can be independently F.

In another embodiment, the present disclosure provides the use of any one of the above compounds of Formula (I) to modulate the activity of the androgen receptor (AR). For example, in some embodiments, the androgen receptor (AR) activity modulation is in a mammalian cell.

In other embodiments, the androgen receptor (AR) activity modulation is for the treatment of at least one indication selected from the group consisting of: prostate cancer, breast cancer, ovarian cancer, endometrial cancer, carcinoma of salivary glands, hair loss, acne, hirsutism, ovarian cysts, polycystic ovarian disease, precocious puberty, spinobulbar muscular atrophy (i.e., Kennedy disease), and age-related macular degeneration. For example, in some embodiments, the indication is prostate cancer. In other embodiments, prostate cancer is castration resistant prostate cancer. While in other embodiments, prostate cancer is androgen dependent prostate cancer.

In other embodiments, the present disclosure provides a method of modulating androgen receptor (AR) activity, the method comprising administering any one of the above compounds of Formula (I), or a pharmaceutically acceptable salt thereof to a subject He needs it.

In other additional embodiments of the above method, the androgen receptor (AR) activity modulation serves to treat one or more of the following: prostate cancer, breast cancer, ovarian cancer, endometrial cancer, carcinoma of Salivary glands, hair loss, acne, hirsutism, ovarian cysts, polycystic ovarian disease, precocious puberty, spinobulbar muscular atrophy, and age-related macular degeneration. For example, in some embodiments, prostate cancer is castration resistant prostate cancer. In other embodiments, prostate cancer is androgen dependent prostate cancer.

In some other embodiments, the present disclosure provides a pharmaceutical composition comprising any one of the above compounds of Formula (I) and a pharmaceutically acceptable carrier.

In yet another embodiment, the present disclosure provides a pharmaceutical composition comprising any one of the above compounds of Formula (I), an additional therapeutic agent and a pharmaceutically acceptable carrier. For example, in some embodiments, the additional therapeutic agent serves for the treatment of prostate cancer, breast cancer, ovarian cancer, endometrial cancer, salivary gland carcinoma, hair loss, acne, hirsutism, ovarian cysts, disease. of polycystic ovary, precocious puberty, spinobulbar muscular atrophy or age-related macular degeneration.

In other embodiments, the additional therapeutic agent is MDV3100, Orteronel (TAK-700), TOK 001; RNA-509; abiraterone acetate, bicalutamide, nilutamide, flutamide, cyproterone acetate, docetaxel, Bevacizumab (Avastin), OSU-HDAC42, VITAXIN, sunitumib, ZD-4054, Cabazitaxel (XRP-6258), MDX-010, Ipilimumab) OGX 011, finasteride, dutasteride, turosteride, bexlosteride, izonsteride, FCE 28260, SKF105,111 or a related compound thereof.

In another embodiment, the present disclosure provides the use of any one of the above pharmaceutical compositions to modulate the activity of the androgen receptor (AR). For example, in some embodiments, the androgen receptor (AR) activity modulation is in a mammalian cell.

In other embodiments, the androgen receptor (AR) activity modulation is for the treatment of at least one indication selected from the group consisting of: prostate cancer, breast cancer, ovarian cancer, endometrial cancer, carcinoma of Salivary glands, hair loss, acne, hirsutism, ovarian cysts, polycystic ovarian disease, precocious puberty, spinobulbar muscular atrophy, and age-related macular degeneration. For example, in some embodiments, the indication is prostate cancer. For example, in some embodiments, prostate cancer is castration resistant prostate cancer, and in other embodiments prostate cancer is androgen dependent prostate cancer.

In yet another embodiment, the present disclosure provides a method of modulating androgen receptor (AR) activity, the method comprising administering any one of the above pharmaceutical compositions to a subject in need thereof. For example, in some embodiments, the androgen receptor (AR) activity modulation is for the treatment of one or more of the following: prostate cancer, breast cancer, ovarian cancer, endometrial cancer, gland carcinoma salivary, hair loss, acne, hirsutism, ovarian cysts, polycystic ovarian disease, precocious puberty, spinobulbar muscular atrophy, and age-related macular degeneration. Even in other embodiments, the indication is prostate cancer. For example, in some embodiments, prostate cancer is castration resistant prostate cancer, while in other embodiments, prostate cancer is androgen dependent prostate cancer.

The compounds described herein are intended to include all racemic mixtures and all individual enantiomers or combinations thereof, whether or not they are specifically represented herein. Alternatively, one or more of the OH groups in the above compounds can be substituted to replace H with a residue selected from Table 1 (ie, to form an OY moiety).

In still other embodiments, the present disclosure provides the use of any of the compounds disclosed herein to modulate the activity of the androgen receptor (AR). For example, in certain embodiments, the androgen receptor (AR) activity modulation is in a mammalian cell.

In other examples, the androgen receptor (AR) activity modulation is for the treatment of at least one indication selected from the group consisting of: prostate cancer, breast cancer, ovarian cancer, endometrial cancer, carcinoma of Salivary glands, hair loss, acne, hirsutism, ovarian cysts, polycystic ovarian disease, precocious puberty, spinobulbar muscular atrophy, and age-related macular degeneration. For example, in certain embodiments, the indication is prostate cancer, for example, castration-resistant prostate cancer. In other examples, prostate cancer is androgen dependent prostate cancer.

The present disclosure also provides a method of modulating androgen receptor (AR) activity, the method comprising administering any of the compounds disclosed herein, or a pharmaceutically acceptable salt thereof, to a subject in need thereof. For example, in certain specific embodiments, the androgen receptor (AR) activity modulation is for the treatment of one or more of the following: prostate cancer, breast cancer, ovarian cancer, endometrial cancer, carcinoma of Salivary glands, hair loss, acne, hirsutism, ovarian cysts, polycystic ovarian disease, precocious puberty, spinobulbar muscular atrophy, and age-related macular degeneration.

The present disclosure also provides a pharmaceutical composition comprising any one or more of the compounds disclosed herein and a pharmaceutically acceptable carrier. The pharmaceutical composition may be to treat one or more of the following: prostate cancer, breast cancer, ovarian cancer, endometrial cancer, salivary gland carcinoma, hair loss, acne, hirsutism, ovarian cysts, ovarian disease polycystic, precocious puberty, spinobulbar muscular atrophy, and age-related macular degeneration.

According to another embodiment, a use of the compounds of Formula (I) is provided as described elsewhere herein for the preparation of a medicament for modulating the androgen receptor (AR).

In accordance with a further embodiment, a screening method is provided for the compounds that modulate the androgen receptor, wherein the screened compounds are selected from the compounds described elsewhere herein.

The androgen receptor (AR) activity modulation can be in a mammalian cell. The androgen receptor (AR) activity modulation can be in a mammal. The mammal can be a human being.

Alternatively, the administration may be to a mammal. Administration may be to a mammal that needs it and in an amount effective for the treatment of at least one indication selected from the group consisting of: prostate cancer, breast cancer, ovarian cancer, endometrial cancer, salivary gland carcinoma , hair loss, acne, hirsutism, ovarian cysts, polycystic ovarian disease, precocious puberty, spinobulbar muscular atrophy (for example, Kennedy disease), and age-related macular degeneration.

The mammalian cell can be a human cell. The modulation of the activity of the AR can be to inhibit the activity of the N-terminal domain of the AR. Modulation of AR activity can be to inhibit AR activity. Modulation can be in vivo. The modulation of AR activity can be for the treatment of at least one indication selected from the group consisting of: prostate cancer, breast cancer, ovarian cancer, endometrial cancer, salivary gland carcinoma, hair loss, acne , hirsutism, ovarian cysts, polycystic ovarian disease, precocious puberty, spinobulbar muscular atrophy (eg, Kennedy disease), and age-related macular degeneration. The indication may be prostate cancer. Prostate cancer can be castration resistant prostate cancer. Prostate cancer can be androgen dependent prostate cancer.

Table 1

Amino acid Remains based on polyethylene glycol and phosphate

Amino acid based residues

(aa) = any naturally occurring amino acid side chain

Remains based on polyethylene glycol

n = 1-200

n = 1-200

Phosphate Based Remains

The remains of TABLE 1 may, for example, and without limitation, be subdivided into three groups: 1) amino acid-based residues; 2) polyethylene glycol based moieties; and 3) phosphate based moieties. In the remains of Table 1 above, the first four residues are amino acid based residues, the fifth and sixth are polyethylene glycol based residues, and the remaining residues are phosphate based residues.

5 Amino acid side chains of naturally occurring amino acids (as often represented herein using "(aa)") are well known to one skilled in the art and can be found in various textbooks, such as "Molecular Cell Biology "by James Darnell et al. Third Edition, published by Scientific American Books in 1995. Often, naturally occurring amino acids are represented by the formula

10 (NH2) C (COOH) (H) (R), where the chemical groups in brackets are each attached to the carbon that is not in brackets. R represents the side chains in this particular formula.

Those skilled in the art will appreciate that the point of covalent attachment of the remainder to the compounds as described herein can, for example, and without limitation, be cleaved under specified conditions. The specified conditions may include, for example, and without limitation, enzymatic or non-enzymatic means in vivo. The cleavage of the remainder can occur, for example, and without limitation, spontaneously, or it can be catalyzed, induced by another agent, or a change in a physical parameter or environmental parameter, for example, an enzyme, light, acid, temperature or pH. . The rest can be, for example, and without limitation, a protective group that acts to mask a functional group, a group that acts as a substrate for one or more active or passive transport mechanisms,

20 or a group that acts to impart or enhance a property of the compound, for example, solubility, bioavailability or localization.

In other particular embodiments of the compounds described elsewhere herein, the compound is a compound selected from one of the compounds in Table 2. 25

Prodrugs are also included within the scope of this disclosure. For example, in one embodiment the hydrogen atom of one or more hydroxyl groups of any of the compounds of Formula I can be replaced with a remainder of Table 1 (ie, to form an OY moiety). Non-limiting examples of such prodrugs include glycine esters and salts thereof as shown below.

In some embodiments, the compounds may be used as described herein or acceptable salts thereof, for the systemic treatment of at least one indication selected from the group consisting of: prostate cancer, breast cancer, ovarian cancer, Endometrial cancer, salivary gland carcinoma, hair loss, acne, hirsutism, ovarian cysts, polycystic ovarian disease, early puberty, spinobulbar muscular atrophy, and age-related macular degeneration. In some embodiments, the compounds as described herein or acceptable salts thereof, may be used in the preparation of a medicament or a composition for the systemic treatment of an indication described herein. In some embodiments, methods for systemically treating any of the indications described herein are also provided. Some aspects of this disclosure take advantage of compositions comprising a compound described herein and a pharmaceutically acceptable carrier or excipient. In some embodiments, prostate cancer is castration resistant prostate cancer (also referred to as hormone refractory, androgen independent, resistant to androgen deprivation, resistant to androgen ablation, independent of androgen depletion, recurrent to castration, recurrent anti-androgen). In some embodiments, prostate cancer is androgen dependent or androgen sensitive. Methods of treatment of any of the indications described herein are also provided. Such methods may include administering a compound as described herein, or a composition of a compound as described herein, or an effective amount of a compound as described herein, or a composition of a compound. as described in this document to a subject who needs it.

The compounds as described herein include all stereoisomers. Accordingly, the compounds include racemic mixtures, enantiomers and diastereomers of any of the compounds described herein.

The compounds as described herein may be in free form or in the form of a salt thereof. In some embodiments, the compounds as described herein may be in the form of a pharmaceutically acceptable salt, which is known in the art (Berge et al., J. Pharm. Sci. 1977, 66, 1). The pharmaceutically acceptable salt as used herein includes, for example, salts that have the desired pharmacological activity of the precursor (salts that retain the biological efficacy and / or properties of the precursor and that are not biological and / or other undesirable mode). Compounds as described herein that have one or more functional groups capable of forming a salt can, for example, be formed as a pharmaceutically acceptable salt. Compounds containing one or more basic functional groups may be capable of forming a pharmaceutically acceptable salt with, for example, a pharmaceutically acceptable organic or inorganic acid. Pharmaceutically acceptable salts may be obtained from, for example, and without limitation, acetic acid, adipic acid, alginic acid, aspartic acid, ascorbic acid, benzoic acid, benzenesulfonic acid, butyric acid, cinnamic acid, citric acid, alkalic acid, Camphorsulfonic acid, cyclopentanepropionic acid, diethylacetic acid, difluconic acid, dodecylsulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, glucoheptanoic acid, gluconic acid, glycerophosphoric acid, glycolic acid, hemisulfonic acid, heptanoic acid, hexanoic acid, hydrochloric acid, hydrochloric acid , iohydric acid, 2-hydroxyethanesulfonic acid, isonicotinic acid, lactic acid, malic acid, maleic acid, malonic acid, mandelic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, ptoluenesulfonic acid, nicotinic acid, nitric acid, oxalic acid, pamoic acid, pectinic acid, 3-phenylpropionic acid, phosphoric acid, picric acid, pimelic acid, pivalic acid, propionic acid, pyruvic acid, salicylic acid, succinic acid, sulfuric acid, sulfamic acid, tartaric acid, thiocyanic acid or undecanoic acid . The

Compounds containing one or more acidic functional groups may be capable of forming pharmaceutically acceptable salts with a pharmaceutically acceptable base, for example, and without limitation, inorganic bases based on alkali metals or alkaline earth metals or organic bases such as primary amine compounds, Secondary amine compounds, tertiary amine compounds, quaternary amine compounds, substituted amines, naturally occurring substituted amines, cyclic amines or basic ion exchange resins. Pharmaceutically acceptable salts may be obtained from, for example, and without limitation, a hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation such as ammonium, sodium, potassium, lithium, calcium, magnesium, iron, zinc, copper , manganese or aluminum, ammonia, benzathine, meglumine, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, isopropylamine, tripropylamine, tributylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethamine, dicyclohexytin, lysinehethylamine, dicyclohexytin, lysinehethylamine, dicyclohexine, lysinehethylamine, dicyclohexine, lysinehethylamine, dicyclohexytin, histine, histine, histine , hydrabamine, choline, betaine, ethylenediamine, glucosamine, glucamine, methylglucamine, theobromo, purines, piperazine, piperidine, procaine, N-ethylpiperidine, theobromo, tetramethylammonium compounds, tetraethylammonium compounds, pyridine, N, N-dimethylaniline, , morpholine, N-methylmorpholine, Netylmorpholine, dicyclohexylamine, dibenzylamine, N, N-dibenzylphenelamine, 1-efenamine, N, N'-dibenziletilend iamine or polyamine resins. In some embodiments, the compounds as described herein may contain both acidic and basic groups and may be in the form of internal salts or zwitterions, for example, and without limitation, betaines. The salts as described herein can be prepared by conventional processes known to a person skilled in the art, for example, and without limitation, by reacting the free form with an organic acid or inorganic acid or base, or by anion exchange or exchange. cationic of other salts. Those skilled in the art will appreciate that the preparation of salts can occur in situ during the isolation and purification of the compounds, or the preparation of salts can be produced by reacting separately an isolated and purified compound.

In some embodiments, the compounds and all different forms thereof (for example, free forms, salts, polymorphs, isomeric forms) as described herein, may be in the form of solvent addition, for example, solvates. Solvates contain stoichiometric or non-stoichiometric amounts of a solvent in physical association of the compound or salt thereof. The solvent may be, for example, and without limitation, a pharmaceutically acceptable solvent. For example, hydrates are formed when the solvent is water or alcoholates are formed when the solvent is an alcohol.

In some embodiments, the compounds and all different forms thereof (eg, free forms, salts, solvates, isomeric forms) as described herein may include crystalline and amorphous forms, for example, polymorphs, pseudopolymorphs, polymorphs conformational, amorphous forms, or a combination thereof. Polymorphs include different packing arrangements of crystals of the same elementary composition of a compound. Polymorphs normally have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability and / or solubility. Those skilled in the art will appreciate that various factors, including the recrystallization solvent, crystallization rate and storage temperature, can cause a single crystalline form to dominate.

In some embodiments, the compounds and all their different forms (eg, free forms, salts, solvates, polymorphs) as described herein include isomers such as geometric isomers, optical isomers based on asymmetric carbon, stereoisomers, tautomers, enantiomers individual, individual diastereomers, racemates, diastereomeric mixtures and combinations thereof, and are not limited by the description of the formula illustrated for convenience.

In some embodiments, the pharmaceutical compositions according to this invention may comprise a salt of said compound, preferably a pharmaceutically or physiologically acceptable salt. Pharmaceutical preparations will normally comprise one or more vehicles, excipients or diluents acceptable for the mode of administration of the preparation, whether by injection, inhalation, topical administration, washing, or other modes suitable for the selected treatment. Suitable carriers, excipients or diluents are those known in the art for use in such modes of administration.

Suitable pharmaceutical compositions can be formulated by means known in the art and their mode of administration and dosage are determined by the skilled person. For parenteral administration, a compound may be dissolved in sterile water or saline or a pharmaceutically acceptable carrier used for the administration of non-water soluble compounds such as those used for vitamin K. For enteral administration, the compound may be administered in a tablet, capsule or dissolved in liquid form. The tablet or capsule may be enteric coated, or in a formulation for sustained release. Many suitable formulations are known, including polymeric or protein microparticles that encapsulate a compound to be released, ointments, pastes, gels, hydrogels, solutions that can be used topically or locally to administer a compound. A sustained release patch or implant can be used to provide the release for a prolonged period of time. Many techniques known to one skilled in the art are described in Remington: the Science & Practice of Pharmacy by Alfonso Gennaro, 20th ed., Lippencott Williams & Wilkins, (2000). Formulations for parenteral administration may, for example, contain excipients, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, or hydrogenated naphthalenes. Be

they can use a biodegradable lactide polymer, a lactide / glycolide copolymer, or polyoxyethylene-polyoxypropylene copolymers to control the release of the compounds. Other parenteral administration systems potentially useful for modulating compounds include ethylene vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems and liposomes. Inhalation formulations may contain excipients, for example, lactose, or they may be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or they may be oily solutions for administration in the form of nasal drops, or as a gel

The compounds or pharmaceutical compositions according to this invention or for use in this invention can be administered by means of a medical device or apparatus such as an implant, a graft, a prosthesis, a stent, etc. Furthermore, it can be conceived that the implants are intended to contain and release said compounds or compositions. An example will be an implant made of a polymeric material adapted to release the compound over a period of time.

An "effective amount" of a pharmaceutical composition according to the invention includes a therapeutically effective amount or a prophylactically effective amount. A "therapeutically effective amount" refers to an amount effective, at doses and for periods of time necessary, to achieve the desired therapeutic result, such as reduction of tumor size, an increase in useful life or an increase in the hope of lifetime. A therapeutically effective amount of a compound may vary according to factors such as the disease status, age, sex and weight of the subject, and the ability of the compound to elicit a desired response in the subject. Dosage regimens can be adjusted to provide the optimal therapeutic response. A therapeutically effective amount is also one in which any toxic or harmful effects of the compound are compensated for the therapeutically beneficial effects. A "prophylactically effective amount" refers to an amount effective, at doses and for periods of time necessary, to achieve the desired prophylactic result, such as smaller tumors, increased lifespan, increased life expectancy or prevention of Progress of prostate cancer to the lethal stage resistant to castration. Normally, a prophylactic dose is used in subjects before or at an earlier stage of the disease, so that a prophylactically effective amount may be less than a therapeutically effective amount.

It should be noted that the dosage values may vary with the severity of the condition to be relieved. For any particular subject, specific dosage regimens can be adjusted over time according to the individual need and professional judgment of the person administering or supervising the administration of the compositions. The dosage ranges set forth herein are examples only and do not limit the dosage ranges that can be selected by doctors. The amount of compound or active compounds in the composition may vary according to factors such as disease status, age, sex and weight of the subject. Dosage regimens can be adjusted to provide the optimal therapeutic response. For example, a single bolus may be administered, several doses divided over time may be administered or the dose may be reduced or increased proportionally as indicated by the requirements of the therapeutic situation. It may be advantageous to formulate parenteral compositions in the form of a dosage unit to facilitate administration and uniformity of the dosage.

In some embodiments, the compounds and all different forms thereof can be used as described herein, for example, and without limitation, together with other methods of treatment for at least one indication selected from the group consisting of: cancer Prostate, breast cancer, ovarian cancer, endometrial cancer, salivary gland carcinoma, hair loss, acne, hirsutism, ovarian cysts, polycystic ovarian disease, precocious puberty, spinobulbar muscle atrophy, and macular degeneration related to age. For example, the compounds and all their different forms as described herein can be used as a neoadjuvant (prior), adjunct (during), and / or adjuvant (after) therapy with surgery, radiation (brachytherapy or external beam ), or other therapies (for example, HIFU), and along with chemotherapies, androgen ablation, antiandrogens or any other therapeutic approach.

With respect to combination therapies, one embodiment of the present disclosure provides a combination of any one or more of a compound of Formula I with one or more currently used or experimental drug therapies that are or can be used to treat any of the foregoing. pathologies (for example, castration-resistant prostate cancer or Kennedy disease). Methods, uses and pharmaceutical compositions comprising the above combination are also provided.

Surprisingly, it has been found that the disclosed compounds, which interfere with the AR primarily through binding to the N-terminus of the AR, demonstrate beneficial synergistic therapeutic effects when used in conjunction with existing approved and developing agents. That is, the biological impact of using the agents together with each other produces a biological and therapeutic effect that is greater than the simple additive effect of each separately.

Accordingly, one embodiment comprises the use of the disclosed compounds in combination therapy with one or more currently used or experimental drug therapies that are used to treat the above pathologies irrespective of the biological mechanism of action of such drug therapies, including, without

limitation, pharmacological therapies that directly or indirectly inhibit the androgen receptor, pharmacological therapies that are cytotoxic and pharmacological therapies that interfere with the production or biological function of androgens (hereinafter, "Other Therapeutic Agents"). By "combination therapy" refers to the administration of any one or more of a compound of Formula I with one or more other therapeutic agent to the same patient so that their pharmacological effects are simultaneous with each other, or if not simultaneous, that their effects are synergistic with each other even if they are dosed sequentially instead of simultaneously.

Such administration includes, without limitation, the dosage of one or more of a compound of Formula I and one or more of the Other Therapeutic Agents as independent agents without any adhesion before dosing, as well as formulations that include one or more of More Other Androgen Blocking Therapeutic Agents mixed with one or more compounds of Formula I as a premixed formulation. Administration of the compound or compounds of Formula I together with Other Therapeutic Agents for the treatment of the above pathologies also includes dosing by any dosage method, including, without limitation, intravenous administration, oral administration, intraperitoneal administration, intramuscular administration or intratumoral administration. .

In another aspect of the present disclosure, the one or more of the Other Therapeutic Agent may be administered to the patient prior to the administration of the compound or compounds of Formula I. In another embodiment, the compound or compounds of Formula I may be co-administered with one or More of the Other Therapeutic Agents. In yet another aspect, the one or more of the Other Therapeutic Agent may be administered to the patient after administration of the compound or compounds of Formula I.

It is completely within the scope of the disclosure that the ratio of the doses of the compound or compounds of Formula I with respect to that of one or more Other Therapeutic Agents may or may not be equal to one and may be varied accordingly to achieve therapeutic benefit. optimum.

For clarity, the compound or compounds of Formula I that are combined with one or more of Other Therapeutic Agents for the improved treatment of the above pathologies may comprise, but not limited to, any compound having a structure of Formula I, including those compounds shown in the Table

2.

The Other Therapeutic Agents include, without limitation, any pharmacological agent that is currently approved by the FDA in the United States (or elsewhere by any other regulatory body) for use as a pharmacological treatment of any of the above pathologies, or used Experimentally today as part of a clinical trial program that is related to previous pathologies. Non-limiting examples of the Other Pharmacological Agents comprise, without limitation: the chemical entity known as MDV3100 (4- (3- (4-cyano-3- (trifluoromethyl) phenyl) -5,5-dimethyl-4-oxo-2 -thioxoimidazolidin-1-yl) -2-fluoro-Nmethylbenzamide) and related compounds, which appears to be a blocker of AR LBD and is currently under development as a treatment for prostate cancer; the chemical entity known as Orteronel (TAK700) and related compounds, which seems to block the synthesis of androgens, the chemical entity known as TOK 001 (Galeterone) and related compounds, which appears to be a blocker of AR LBD, and a CYP17 lyase inhibitor , and also seems to decrease levels of total androgen receptors in prostate cancer cells. TOK 001 is currently under development as a treatment for prostate cancer; the chemical entity known as RNA509 and related compounds, which appears to be a blocker of AR LBD and is currently under development as a treatment for prostate cancer; the chemical entity known as abiraterone acetate (or CB-7630; (3S, 8R, 9S, 10R, 13S, 14S) -10,13-dimethyl-17- (pyridin-3-yl) 2,3,4,7 , 8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta [a] phenanthren-3-ol), and related molecules, which seems to block the production of androgen and is currently under development for the prostate cancer treatment; the chemical entity known as bicalutamide (N- [4-cyano-3- (trifluoromethyl) phenyl] -3 - [(4-fluorophenyl) sulfonyl] -2-hydroxy-2-methylpropanamide) and related compounds, which appears to be an AR blocker LBD and currently used to treat prostate cancer, the chemical entity known as nilutamide (5,5-dimethyl-3- [4-nitro-3 (trifluoromethyl) phenyl] imidazolidin-2,4-dione) and related compounds , which appears to be a blocker of AR LBD and is currently used to treat prostate cancer, the chemical entity known as flutamide (2-methyl-N- [4nitro-3- (trifluoromethyl) phenyl] -propanamide) and related compounds , which appears to be a blocker of AR LBD and is currently used to treat prostate cancer, the chemical entities known as cyproterone acetate (6-chloro-1β, 2β-dihydro-17-hydroxy-3'H-cyclopropa [ 1,2] pregna-4,6-diene-3,20-dione) and related compounds, which appears to be a blocker of AR LBD and is currently used to treat c prostate cancer, the chemical entity known as docetaxel (Taxotere; 1,7β, 10β-trihydroxy-9-oxo-5β, 20-epoxitax-11-eno-2a, 4.13atriyl 4-acetate 2-benzoate 13 - {(2R, 3S) -3 - [(tert-butoxycarbonyl) amino] -2-hydroxy-3-phenylpropanoate}) and related compounds, which appears to be a cytotoxic antimicrotubule agent and is currently used together with prednisone to treat prostate cancer, the chemical entity known as Bevacizumab (Avastin), a monoclonal antibody which recognizes and blocks vascular endothelial growth factor A (VEGF-A) and can be used to treat prostate cancer, the chemical entity known as OSUHDAC42 ((S) - (+) - N-hydroxy-4- (3- methyl-2-phenylbutyrylamino) benzamide), and related compounds, which appears to act as a histone deacetylase inhibitor, and which is currently under development as a treatment for prostate cancer, the chemical entity known as

VITAXIN that appears to be a monoclonal antibody against vascular integrin ανβ3 to prevent angiogenesis, and that can be used to treat prostate cancer, the chemical entity known as sunitumib (N- (2-diethylaminoethyl) -5 - [(Z) - (5 -fluoro-2-oxo-1H-indole-3-ylidene) methyl] -2,4-dimethyl-1H-pyrrol-3-carboxamide) and related compounds, which appears to inhibit the multiple tyrosine kinase receptor (RTK) and may used for the treatment of prostate cancer, the chemical entity known as ZD4054 (N- (3-Methoxy-5-methylpyrazin-2-yl) -2- [4- (1,3,4oxadiazol-2-yl) phenyl] pyridin-3-sulfonamid) and related compounds, which seems to block the edta receptor and that can be used for the treatment of prostate cancer, the chemical entity known as Cabazitaxel (XRP6258), and related compounds, which appears to be a cytotoxic microtubule inhibitor , and that is currently used to treat prostate cancer; the chemical entity known as MDX010 (Ipilimumab), a complete human monoclonal antibody that binds to and blocks the activity of CTLA-4 that is currently under development as an immunotherapeutic agent for the treatment of prostate cancer; the chemical entity known as OGX 427 that appears to direct HSP27 as an antisense agent, and is currently under development for the treatment of prostate cancer; the chemical entity known as OGX 011 that seems to direct clusterin as an antisense agent, and is currently under development as a treatment for prostate cancer; the chemical entity known as finasteride (Proscar, Propecia; N- (1,1-dimethylethyl) -3-oxo- (5α, 17β) -4azaandrost-1-eno-17-carboxamide), and related compounds, which appears to be a 5-alpha reductase inhibitor that reduces dihydrotestosterone levels, and can be used to treat prostate cancer; the chemical entity known as dutasteride (Avodart; 5α, 17β) -N- {2,5 bis (trifluoromethyl) phenyl} -3-oxo-4-azaandrost-1-eno-17carboxamide) and related molecules, which appears to be an inhibitor of 5-alpha reductase that reduces dihydrotestosterone levels, and can be used in the treatment of prostate cancer; the chemical entity known as turosteride ((4aR, 4bS, 6aS, 7S, 9aS, 9bS, 11aR) -1,4a, 6a-trimethyl-2-oxo-N- (propan-2-yl) -N- (propan- 2-Carbamoyl) hexadecahydro-1H-indene [5,4-f] quinolin-7-carboxamide), and related molecules, which appears to be a 5-alpha reductase inhibitor that reduces dihydrotestosterone levels and can be used in cancer treatment prostate; the chemical entity known as bexlosteride (LY-191.704; (4aS, 10bR) -8-chloro-4-methyl1,2,4a, 5,6,10b-hexahydrobenzo [f] quinolin-3-one), and related compounds, which appears to be a 5-alpha reductase inhibitor that reduces dihydrotestosterone levels and can be used in the treatment of prostate cancer; the chemical entity known as izonsteride (LY-320,236; (4aR, 10bR) -8 - [(4-ethyl-1,3-benzothiazol-2-yl) sulfanyl] -4,10bdimethyl-1,4,4a, 5, 6,10b-hexahydrobenzo [f] quinolin-3 (2H) -one) and related compounds, which appears to be a 5-alpha reductase inhibitor that reduces dihydrotestosterone levels and can be used for the treatment of prostate cancer; the chemical entity known as FCE 28260 and related compounds, which appears to be a 5-alpha reductase inhibitor that reduces dihydrotestosterone levels and can be used for the treatment of prostate cancer; the chemical entity known as SKF105,111, and related compounds, which appears to be a 5-alpha reductase inhibitor that reduces dihydrotestosterone levels and can be used for the treatment of prostate cancer.

In general, the compounds of the invention should be used without causing substantial toxicity. The toxicity of the compounds of the invention can be determined using conventional techniques, for example, by testing cell cultures or experimental animals and determining the therapeutic index, that is, the ratio between LD50 (the lethal dose for 50% of the population) and the LD100 (the lethal dose for 100% of the population). However, in some circumstances, such as in serious illness conditions, it may be necessary to administer substantial excesses of the compositions. Some compounds of this invention may be toxic in certain concentrations. Titration studies can be used to determine toxic and non-toxic concentrations. Toxicity can be assessed by examining the specificity of a particular compound or composition through cell lines that use PC3 cells as a negative control that do not express functional AR. Animal studies can be used to provide an indication of whether the compound has any effect on other tissues. Systemic therapy that targets AR will not cause major problems to other tissues, since antiandrogens and androgen insensitivity syndrome are not fatal.

Compounds as described herein can be administered to a subject. As used herein, a "subject" may be a human being, a non-human primate, a mammal, rat, mouse, cow, horse, pig, sheep, goat, dog, cat and the like. The subject may be suspected of having or being at risk of having a cancer, such as prostate cancer, breast cancer, ovarian cancer, salivary gland carcinoma,

or endometrial cancer, or being suspected of having or being at risk of acne, hirsutism, alopecia, benign prostatic hyperplasia, ovarian cysts, polycystic ovarian disease, precocious puberty, spinobulbar muscle atrophy, or age-related macular degeneration. Diagnostic methods for various cancers, such as prostate cancer, breast cancer, ovarian cancer, salivary gland carcinoma, or endometrial cancer, and diagnostic methods for acne, hirsutism, alopecia, benign prostatic hyperplasia, ovarian cysts , polycystic ovarian disease, precocious puberty, spinobulbar muscular atrophy, or age-related macular degeneration and clinical delineation of cancer diagnoses, such as prostate cancer, breast cancer, ovarian cancer, salivary gland carcinoma, or cancer of endometrium, and clinical delineation of acne, hirsutism, alopecia, benign prostatic hyperplasia, ovarian cysts, polycystic ovarian disease, precocious puberty, spinobulbar muscular atrophy, or age-related macular degeneration are known to those skilled in the art.

The compounds described herein can be used for the treatment of at least one indication selected from the group consisting of: prostate cancer, breast cancer, ovarian cancer, cancer of

endometrium, salivary gland carcinoma, hair loss, acne, hirsutism, ovarian cysts, polycystic ovarian disease, early puberty, spinobulbar muscle atrophy, and age-related macular degeneration. The compounds described herein can be used for the treatment of prostate cancer. The compounds described herein can be used for the treatment of castration-resistant prostate cancer. The compounds described herein can be used for the treatment of androgen-dependent prostate cancer. The compounds described herein can be used for the preparation of a medicament for the treatment of at least one indication selected from the group consisting of: prostate cancer, breast cancer, ovarian cancer, endometrial cancer, salivary gland carcinoma , hair loss, acne, hirsutism, ovarian cysts, polycystic ovarian disease, precocious puberty, spinobulbar muscle atrophy, and age-related macular degeneration. The compounds described herein can be used for the preparation of a medicament for the treatment of prostate cancer. The compounds described herein can be used for the preparation of a medicament for the treatment of castration-resistant prostate cancer. The compounds described herein can be used for the preparation of a medicament for the treatment of androgen-dependent prostate cancer. The compounds described herein can be used in a method for the treatment of at least one indication selected from the group consisting of: prostate cancer, breast cancer, ovarian cancer, endometrial cancer, salivary gland carcinoma, loss of the hair, acne, hirsutism, ovarian cysts, polycystic ovarian disease, precocious puberty, spinobulbar muscular atrophy, and age-related macular degeneration. The method may comprise administering an effective amount of a compound described herein to a subject in need thereof. The compounds described herein can be used in a method of treating prostate cancer, the method comprising administering to an individual in need thereof an effective amount of a compound described herein. The compounds described herein can be used in a method of treatment of castration-resistant prostate cancer, the method comprising administering to an individual in need thereof an effective amount of a compound described herein. The compounds described herein can be used in an androgen-dependent prostate cancer treatment method, the method comprising administering to an individual in need thereof an effective amount of a compound described herein.

The compounds described herein can also be used in assays and for research purposes. The definitions used include androgen receptor ligand-dependent activation (AR) by androgens such as dihydrotestosterone (DHT) or synthetic androgen (R1881) used for research purposes. Ligand-dependent activation of AR refers to transactivation of AR in the absence of androgen (ligand), for example, by stimulating the cAMP-dependent protein kinase (PKA) pathway with forskolin (FSK). Some compounds and compositions of this invention can inhibit both the induction of FSK and androgen (eg, R1881) of ARE-luciferase (ARE-luc). The constitutive activity of AR refers to a splice variant that lacks the ligand binding domain of AR. Such compounds may block a mechanism that is common both for ligand-dependent activation and for independent ligand activation of the AR, as well as for constitutively active splicing variants of the AR that lack ligand binding domain. This may involve any stage in the activation of RA, including the dissociation of heat shock proteins, essential post-translational modifications (eg, acetylation, phosphorylation), nuclear translocation, protein-protein interactions, formation of the transcriptional complex, release of co-repressors , and / or an increase in degradation. Such compounds and compositions of this invention may inhibit ligand-only activity and may interfere with a specific mechanism for ligand-dependent activation (eg, accessibility of the ligand binding domain (LBD) to androgen). Numerous disorders, in addition to prostate cancer, involve the androgenic axis (for example, acne, hirsutism, alopecia, benign prostatic hyperplasia) and compounds that interfere with this mechanism can be used to treat such conditions. Some compounds and compositions of this invention may inhibit only the induction of FSK and may be specific inhibitors for independent ligand activation of AR. These compounds and compositions may interfere with the cascade of events that normally occur with the activity of FSK and / or PKA or any downstream effect that may have a function on the AR (for example, FSK increases MAPK activity that has a potent effect on AR activity). Examples may include an inhibitor of cAMP and / or PKA or other kinases. Some compounds and compositions of this invention can induce basal levels of AR activity (without androgens or PKA pathway stimulation). Some compounds and compositions of this invention may increase induction by R1881 or FSK. Such compounds and compositions can stimulate transcription or transactivation of AR. Some compounds and compositions of this invention may inhibit androgen receptor activity. Interleukin-6 (IL-6) also causes independent ligand activation of AR in LNCaP cells and can be used in addition to FSK.

Compounds for use in the present invention can be obtained from medical sources or modified using known methodologies from compounds of natural origin. In addition, the methods of preparing or synthesizing compounds of the present invention will be understood by one skilled in the art that has reference to known chemical synthesis principles. For example, Auzou et al 1974 European Journal of Medicinal Chemistry 9 (5), 548-554 describes suitable synthetic procedures that can be adequately considered and adapted to prepare the compounds of any one of Formula I to XXI as set forth above. Other references that may be useful include: Debasish Das, Jyh-Fu Lee and Soofin Cheng

"Sulfonic acid functionalized mesoporous MCM-41 silica as a convenient catalyst for Bisphenol-A synthesis" Chemical Communications, (2001) 2178-2179; US Patent 2571217 Davis, Orris L .; Knight, Horace S .; Skinner, John R. (Shell Development Co.) "Halohydrin ethers of phenols." (1951); and Rokicki, G .; Pawlicki, J .; Kuran, W. "Reactions of 4-chloromethyl-1,3-dioxolan-2-one with phenols as a new route to polyols and cyclic carbonates." Journal fuer Praktische Chemie (Leipzig) (1985) 327, 718-722.

For example, the compounds of the present invention can be prepared with reference to the following General Reaction Scheme I:

10 Referring to Synthetic Scheme 1, compounds of structure A can be purchased from commercial sources or prepared according to methods known in the art. The reaction of A with an appropriately substituted 1,3-dioxolane, in which X is an appropriate leaving group (eg, chlorine), produces compounds of structure B. Optically pure or racemic dioxolanes can be employed to produce the stereochemistry

15 desired. Epoxidation of B with an appropriate reagent, for example an appropriately substituted glycidyl tosylate, results in compounds of structure C. Various epoxidation reagents can be employed, including optically pure reagents that produce optically pure epoxides (eg, + or -tosylate of glycidyl). Treatment of C with an appropriate ring opening reagent, for example CeCl3x7H2O, produces D.

The fluorination of D results in F. Methods for such fluorination are well known. For example, in one embodiment, a fluorine atom is introduced by treatment with diethylamino sulfur fluoride (DAST) or Xtalfluor-E or M (see J. Org. Chem. 2010, 75, 3401-3411). In other embodiments, the D-hydroxyl moiety can be converted into an appropriate leaving group, for example, by reaction with tosyl chloride or mesyl anhydride followed by

reaction with [K + / 2,2,2-crypto] Tetrabutylammonium fluoride. Other methods for fluorination of D are known to those skilled in the art. For descriptions of fluoridation procedures, see J. Org. Chem. 2010, 75, 3401-3411, Bioorg. Med. Chem. 2009, 17, 7441-7448, and J. Med. Chem. 1990, 33, 2430-2437,

One skilled in the art will recognize that variations are possible in the order of the stages and reagents analyzed in reference to Synthetic Scheme I. For example, epoxidation may precede dioxalone formation. In addition, fluorine atoms can be introduced through any number of reagents, and fluorination is not limited to the methods depicted or described above. The methods for such fluorination are well known in the art. Finally, prodrugs of Formula I can be prepared by functionalizing a free hydroxyl in structure D or F. Methods for such functionalization are well known in the art, for example, reaction with an acid chloride analog of a residue of Table 1 or any other suitable reagent. The methodologies for the preparation of compounds of Formula I are described in more detail in the following non-limiting example schemes.

Various alternative embodiments and examples of the invention are described herein. These embodiments and examples are illustrative and should not be construed as limiting the scope of the invention.

Examples

Examples that do not belong to the invention are for illustrative purposes only.

All non-aqueous reactions were performed in round-bottomed flame dried flasks. The flasks were equipped with a rubber stopper and the reactions were carried out under positive argon pressure, unless otherwise indicated. Stainless steel syringes were used to transfer sensitive liquids to air and moisture. Flash column chromatography was performed as described by Still et al. (Still, W. C .; Kahn, M .; Mitra, A. J. Org. Chem. 1978, 43, 2923) using 230-400 mesh silica gel. Thin layer chromatography was performed using pre-coated aluminum plates with 0.25 mm silica gel 230-400 mesh impregnated with a fluorescent indicator (254 nm). The thin layer chromatography plates were visualized by exposure to ultraviolet light and a "Seebach" staining solution (700 ml of water, 10.5 g of cerium (IV) sulfate tetrahydrate, 15.0 g of molybdate of phosphoric acid, 17.5 g of sulfuric acid) followed by heating (~ 1 min) with a heat gun (~ 250 ° C). The organic solutions were concentrated in Büchi R-114 rotary evaporators under reduced pressure (15-30 torr, homemade vacuum) at 25-40 ° C.

Commercial reagents and solvents were used as received. All solvents used for extraction and chromatography were of HPLC quality. Seppaks ™ of normal phase silica gel were purchased from Waters, Inc. The thin layer chromatography plates were Kieselgel 60F254. All reagents were purchased from Sigma Aldrich and Fisher Scientific Canada.

Proton nuclear magnetic resonance spectra (1 H NMR) were recorded at 25 ° C using a Bruker 400 reverse probe spectrometer and Bruker 400 spectrometers, indicated in parts per million on the δ scale, and referenced from the residual protium in the NMR solvent (DMSO-d6: δ 2.50 (DMSO-d5), CDCl3: δ 7.24 (CHCl3)). Carbon-13 nuclear magnetic resonance spectra (13C NMR) were recorded with a Bruker 400 spectrometer, indicated in parts per million on the δ scale, and referenced from the carbon resonances of the solvent (DMSO-d6: δ 39.51, CDCl3: δ 77.00). The spectral characteristics are represented in table form in the following order: chemical shift (δ, ppm); multiplicity (s = singlet, d = doublet, t = triplet, m = multiplet, a = width); coupling constant (J, Hz, number of protons).

LNCaP cells were initially used for all experiments because they are well differentiated human prostate cancer cells in which the independent activation of AR ligand by FSK has been characterized (Nazareth et al 1996 J. Biol. Chem. 271, 19900- 19907; and Sadar 1999 J. Biol. Chem. 274, 7777-7783). LNCaP cells express endogenous AR and secrete prostate specific antigen (PSA) (Horoszewicz et al 1983 Cancer Res. 43, 1809-1818). LNCaP cells can develop as monolayers in cell culture or as tumors in the well-characterized xenograft model that advances to castration resistance in castrated hosts (Sato et al 1996 J. Steroid Biochem. Mol. Biol. 58, 139-146 ; Gleave et al 1991 Cancer Res. 51, 3753-3761; Sato et al 1997 Cancer Res. 57, 1584-1589; and Sadar et al 2002 Mol. Cancer Ther. 1 (8), 629-637). R1881 was used as it is stable and avoids problems associated with the labile physiological ligand dihydrotestosterone (DHT). The specificity of the indicator can be determined using several alternative indicator gene constructs. Some well-characterized ARE-driven gene constructs that have been widely used are the PSA promoter (6.1 kb) that contains several ARE and is highly inducible by androgens, as well as FSK (Ueda et al 2002 A J Biol. Chem. 277, 7076-7085) and ARR3-thymidine kinase (tk) -luciferase, which is an artificial indicator construct that contains three tandem repeats of the rat probasin ARE1 and upstream regions of a Luciferase indicator (Snoek et al 1996 J. Steroid Biochem. Mol. Biol. 59, 243-250).

Example 1

SYNTHESIS OF (S) -4- (2- (4 - ((2,2-DIMETHYL-1,3-DIOXOLAN-4-IL) METOXI) PHENYL) PROPAN-2-IL) PHENOL (A)

Sodium hydride (60% dispersion in mineral oil, 1750 mg, 43.80 mmol, 1.0 equiv.) Was slowly added to a stirred solution of Bisphenol A (10,000 mg, 43.80 mmol, 1 equiv.) In dimethyl anhydrous formamide (30 ml), at room temperature, and the content was stirred under an argon atmosphere for 20 min. (R) - (+) - 4% Chloromethyl-2,2-dimethyl-1,3-dioxolane (7.10 ml, 52.56 mmol, 1.2 equiv.) Was added by syringe and the mixture was left react at 70-80 ° C for 40 h. Warning! The use of sodium hydride in hot N, N dimethylformamide can result in deflagration and fire. Then, the reaction was stopped by the addition of a saturated solution of ammonium chloride (10 ml), and the mixture was extracted with ethyl acetate (3 x 20 ml). The organic layer was washed with deionized water (25 ml), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (eluent: 10% ethyl acetate in hexane) to provide compound (a) (2S) (3560 mg, 24%, 25-30% conversion) in the form of a foam. Other stereoisomers (including racemic isomers) can be prepared starting from the appropriate dioxolane reagent. 1H NMR (400 MHz, CDCl3): δ 7.15-7.13 (m, 2H), 7.08-7.06 (m, 2H), 6.82-6.80 (m, 2H), 6 , 75-6.74 (m, 2H), 4.50-4.45 (m, 1H), 4.19-4.15 (dd, J = 8.4, 6.4, 1H), 4, 07-4.03 (dd, J = 9.6, 5.6, 1H), 3.94-3.88 (m, 2H), 1.63 (s, 6H), 1.47 (s, 3H ), 1.41 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 156.5, 153.9, 143.9, 142.9, 128.0, 127.9, 114.9, 114.9, 114.0, 109.9, 74.2, 68.9, 67.1, 41.8, 31.2, 26.9, 25.5; HRMS (ESI) (m / z): calc. for C21H27O4 [M + H] +: 343,1909, observed: 343,1904.

Example 2

SYNTHESIS OF (S) -2,2-DIMETHYL-4 - ((4- (2- (4 - ((R) -OXIRAN-2-ILMETOXI) PHENYL) PROPAN-2-IL) PHENOXY) METHYL) -1, 3-DIOXOLANE (B)

Sodium hydride (60% dispersion in mineral oil, 391 mg, 9.78 mmol, 1.5 equiv.) Was slowly added to a stirred solution of derivative (a) (2230 mg, 6.52 mmol, 1 equiv.) in anhydrous dimethyl formamide (15 ml), at room temperature, and the content was stirred under an argon atmosphere for 30 min. A solution of (2R) - (-) - 98% glycidyl tosylate (2230 mg, 9.78 mmol, 1.5 equiv.) In anhydrous dimethyl formamide (5 ml) was added by syringe, and the mixture was left react at room temperature for 16 h. Then, the reaction was stopped by the addition of a saturated solution of ammonium chloride (10 ml), and the mixture was extracted with ethyl acetate (3 x 20 ml). The organic layer was washed with deionized water (20 ml), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (eluent: 20% to 40% ethyl acetate in hexane) to provide (b) (2S, 20R) (2.53 g, 94%) as of a transparent foam. Other diastereomers or racemic mixtures are prepared using an appropriate tosylate. 1H NMR (400 MHz, DMSO-d6): δ 7.11-7.08 (dd, J = 8.8, 1.2, 4H), 6.85-6.82 (dd, J = 6.4 , 3,2, 4H), 4,414.35 (m, 1H), 4.28-4.25 (dd, J = 11.2, 2.4, 1H), 4.09-4.06 (dd, J = 8.4, 6.8, 1H), 3.95-3.94 (m, 2H), 3.81-3.72 (m, 2H), 3.32-3.29 (m, 1H ), 2.82 (t, J = 4.8, 1H), 2.69-2.67 (dd, J = 4.8, 2.4, 1H), 1.57 (s, 6H), 1 , 35 (s, 3H), 1.29 (s, 3H); 13C NMR (100 MHz, DMSO-d6): δ 156.1, 156.0, 142.9, 142.8, 127.4, 113.9, 113.8, 108.8, 73.7, 68, 8, 68.6, 65.8, 49.7, 43.7, 41.2, 30.7, 26.6, 25.4; HRMS (ESI) (m / z): calc. for C24H30O5Na [M + Na] +: 421.1991, observed: 421.1986.

Example 3

SYNTHESIS OF (R) -3- (4- (2- (4 - ((S) -4-CHLORINE-3-HYDROXIBUTE) PHENYL) PROPAN-2-IL) PHENOXY) PROPAN-1,2-DIOL (C)

To a solution of derivative (b) (2530 mg, 6.34 mmol, 1 equiv.) In acetonitrile (25 ml) was added CeCl3 · 7H2O (5910 mg, 15.87 mmol, 2.5 equiv.), And The mixture was heated at reflux for 20 h. The resulting white paste was filtered and washed with ethyl acetate, and the clear suspension was concentrated under reduced pressure. The residue

The resulting 10 was purified by flash column chromatography on silica gel (eluent: 20% hexane in ethyl acetate to 100% ethyl acetate) and Sep pak from Si gel (10 g, eluent: 50% hexane in ethyl acetate to 80% ethyl acetate) to provide (c) (2R, 20S) (2250 mg, 90%) as a clear foam. 1H NMR (400 MHz, DMSO-d6): δ 7.09 (dd, J = 8.8, 4.0, 4H), 6.82 (t, J = 8.4, 4H), 5.52 ( d, J = 5.2, 1H), 4.90 (d, J = 4.8, 1H), 4.63 (t, J = 5.6, 1H), 4.03-3.98 (m , 1H), 3.96-3.92 (m, 3H), 3.82-3.72 (m, 3H), 3.67-3.63 (dd, J =

11.2, 5.6, 1H), 3.42 (t, J = 6.0, 2H), 1.57 (s, 6H); 13C NMR (100 MHz, DMSO-d6): δ 156.5, 156.1, 142.9, 142.4, 127.4, 127.4, 113.9, 113.8, 69.9, 69, 4, 68.8, 68.6, 62.7, 46.8, 41.1, 30.7; HRMS (ESI) (m / z): calc. for C21H27O5NaCl [M + Na] +: 417.1445, observed: 417.1440,

Example 4

20 SYNTHESIS OF (S) -1-CHLORINE-4- (4- (2- (4 - ((S) -3-FLUORO-2-HYDROXYPROPOXI) PHENYL) PROPAN-2-IL) PHENYL) BUTAN-2-OL (1 C)

To a solution of (c) (100 mg, 0.25 mmol) in dichloromethane (2.0 ml), triethylamine trifluorhydrate (84 µl, 0.51 mmol) and XTalFluor-M (123 mg, 0, were successively added 51 mmol). After 3 h, the reaction mixture was quenched at room temperature with a 5% aqueous solution of sodium bicarbonate and stirred for 15 min, and the resulting mixture was extracted twice with dichloromethane. The organic phases were combined, dried over

Anhydrous magnesium sulfate and filtered. The solvents were evaporated, and the resulting crude material was purified by silica gel flash chromatography (eluent: 0-5% ethyl acetate in dichloromethane) to provide (1c) (17 mg, 17%) as a foam Pale color 1H NMR (400 MHz, DMSO-d6): δ 7.09 (d, J = 8.4, 4H), 6.83 (d, J = 8.4, 4H), 5.52 (d, J = 5.2, 1H), 5.41 (d, J = 5.2, 1H), 4.56-4.48 (ddd, J = 18.8, 9.2, 3.6, 1H), 4 , 45-4.36 (ddd, J = 19.2, 10.0, 4.0, 1H), 4.05-3.97 (m, 2H), 3.93-3.90 (m, 4H ), 3.75-3.72 (dd, J = 10.8, 4.0, 1H), 3.67

3.63 (dd, J = 11.2.5.2, 1H), 1.57 (s, 6H); 19 F NMR (282 MHz, CDCl 3): δ -232.8-233.2 (td, J = -47.9, -19.7, 1F); 19F NMR decoupling 1H (282 MHz, CDCl3): δ -233.0 (s, 1F); 13C NMR (100 MHz, DMSO-d6): δ 156.1, 142.8, 127.4, 113.9, 85.3, 83.6 (d, J = 166.0), 68.9, 68 , 6, 68.0, 67.9 (d, J = 8.0), 67.7, 67.5 (d, J = 20.0), 46.8, 41.2, 30.7,

Different stereoisomers were prepared according to the above procedures (ie, Examples 1-4) using the appropriate chiral reagent.

Example 5

INHIBITION OF THE ANDROGEN DEPENDENT PROLIFERATION

As observed in Example 9, the comparative compound (Ac) is the most potent and least toxic of the comparative compounds (ie, compounds lacking the chlorine and fluorine substituents of Formula (I)). Accordingly, a series of experiments were designed to evaluate the potency and toxicity of various compounds of Formula (I) with respect to comparative compound (Ac). For this purpose, proliferation dependent on

50 androgens of LNCaP cells treated with 0.1 nM R1881 for 3 days compared to the viability of PC3 cells at 2 days with increasing concentrations of comparative compound (Ac) or compound 1 using the AlamarBlue Proliferation Assay. LNCaP human prostate cancer cells were maintained in a medium

RPMI 1640 free of phenol red with 0.5% bovine fetal serum (v / v), while PC3 prostate human cancer cells were grown in DMEM red phenol medium with 0.5% bovine fetal serum (v / v) at 37 ° C. The cells were seeded in 96-well plates for 24 h before pretreatment for 1 h with comparative compound (Ac) or compound 1 followed by the addition of 0.1 nM R1881 (synthetic androgen) to LNCaP cells. LNCaP cells were incubated for 72 hours with R1881, while the duration of the experiment was 48 hours for PC3 cells. AlamarBlue reagent was added to the cells before incubation and fluorescence measurement at 570 nm.

Figures 1A and 1B present data from the previous experiment. Inspection of Figures 1A and 1B shows that compound 1 inhibits androgen-dependent proliferation of LNCaP cells at lower concentrations (i.e., more potent inhibitor) compared to comparative compound (Ac).

Example 6

INHIBITION OF THE TRANSACTIVATION OF THE N-TERMINAL DOMAIN OF THE ANDROGENIC RECEIVER

Inhibition of transactivation of the N-terminal domain of the androgenic receptor was determined as follows. LNCaP cells were co-transfected with 5xGA14UAS-TATA-luciferase and AR (1-558) -Gal4DBD before preincubation with the indicated concentrations of comparative compound (Ac) (25 µm) or EPI-0011 compound 1 (20 µm) and then were treated with 50 ng / ml of interleukin-6 (IL-6) or BSA (control bovine serum albumin). The data in Figure 2 demonstrate the most potent inhibition activity of compound 1 with respect to comparative compound (Ac).

Example 7

INHIBITION OF TUMOR GROWTH

The inhibition of the growth of VCaP xenografts in castrated mice was determined as follows. Male NOD-SCID mice that had subcutaneous VCaP tumors were castrated when the tumor volume was ~ 100 mm3. Seven days after castration, guests were injected intravenously with 50 mg / kg body weight of comparative compound (Ac), compound 1, compound 1c or compound 1d on alternate days for a total of seven doses . The experiment ended two days after the last dose. The change in tumor volume was determined as the change on day 14 compared to the day of the 1st injection. DMSO was used as the control vehicle.

Growth curves of VCaP xenografts in castrated mice determined in accordance with the above experiments are shown in Figure 3. Figure 4 represents the change in tumor volume on day 14. All mice treated with compounds 1, 1c and 1d experienced an increase in tumor volume loss compared to mice treated with the comparative compound (Ac).

Example 8

CHANGE OF BODY WEIGHT

The effects of the compounds on the animal's body weight were determined as indicated below. Male NOD-SCID mice that had subcutaneous VCaP tumors were castrated when the tumor volume was ~ 100 mm3. Seven days after castration, guests were injected intravenously with 50 mg / kg body weight of comparative compound (Ac), compound 1, compound 1c or compound 1d on alternate days for a total of seven doses . The experiment ended two days after the last dose. The change in body weight represents the change on day 14 compared to the day of the 1st injection of the compounds. DMSO was used as the control vehicle. The results are presented in Figure 5.

Example 9

ACTIVITY OF COMPARATIVE COMPOUNDS

For comparison, the activity of a compound lacking the chlorine and fluorine substitution of Formula I, and each of its stereoisomers was determined. The comparative compounds had the following structures (A), (Aa), (Ab), (Ac) and (Ad):

Dose-response curves were used using a PSA-luciferase indicator assay to calculate IC50 values for comparative compound (A) and each of its stereoisomers. The specificity of the indicator was investigated using AR-driven indicator gene constructs that included indicators of PSA, probasin (PB)

10 and ARR3-luciferase. All stereoisomers inhibited the transcriptional activity of AR as measured using these indicators. As seen in Table 3, the comparative compound (Ac) has the best activity of all the comparative compounds.

Table 3

Activity of comparative compounds

Compound

IC50 (uM) mean ± SD PSA-Luc activity (%) mean ± SD PB-Luc activity (%) mean ± SD ARR3-Luc activity (%) mean ± SD

(TO)

12.63 ± 4.33 36.91 ± 16.46 63.96 ± 13.70 63.96 ± 14.57

(Aa)

13.78 ± 0.66 45.16 ± 29.13 66.44 ± 12.47 66.44 ± 31.59

(Ab)

10.95 ± 4.79 24.49 ± 13.20 43.70 ± 9.98 43.68 ± 15.16

(Ac)

7.40 ± 1.46 * 24.33 ± 13.63 41.58 ± 6.63 41.58 ± 14.82

(Ad)

17.08 ± 3.49 33.55 ± 11.31 54.72 ± 7.83 54.73 ± 12.99

* (Ac) vs. (Ad) p = 0.00571; (Ac) vs. (Aa) p = 0.00116

15 To determine whether these in vitro responses can predict superior antitumor activity in vivo, the CRPC LNCaP xenograft model was used. Data were obtained as described in Examples 5-8. All comparative compounds inhibited CRPC tumor growth compared to the DMSO control (Figure 6). According to the responses in vitro, the comparative compound (Ac), as well as the compound

Comparative (Ab) had better antitumor activity compared to comparative compounds (Ad) and (Aa) (Figure 7). Tumor regression was achieved in 60% of the animals treated with (Ac) and (Ab), although (Ac) caused a greater regression (Figure 8). No loss of body weight was observed in animals treated with (Ac), while (Ab) had some losses (Figure 9). Therefore, the comparative compound (Ac) is the most potent and least toxic of the comparative compounds.

25 The numerical intervals include the numbers that define the interval. The term "comprising" is used herein as an open term, substantially equivalent to the expression "including, but not limited to," and the word "comprises" has a corresponding meaning. As used herein, the singular forms "a", "a" and "the" include plural references, unless the context clearly dictates

30 something else. Therefore, for example, the reference to "one thing" includes more than one such thing. Mention of references herein is not an admission that such references are prior art of the present invention.

Claims (13)

1. A compound that has a structure of Formula I: or a pharmaceutically acceptable salt or stereoisomer thereof, in which: R1 is F, OH or OY; R2, R3 R5, R6, R7 and R9 are each independently H or F; R4 is H, F, OH or OY; R8 is OH or OY; R10 and R11 are each independently F or C1-C5 alkyl; and Y is a moiety selected from: or in which (aa) is any naturally occurring amino acid side chain and n is an integer between 1-200; 5 where at least one of R1, R2, R3, R4 or R5 is F. 2. The compound of claim 1, wherein the compound has one of the following structures (Ia), (Ib), (Ic) or (Id): 10 3. The compound of claim 1, wherein the compound has one of the following structures: or 15 or a pharmaceutically acceptable salt or stereoisomer thereof. 4. The compound of claim 1, wherein the compound has the following structure (4): or a pharmaceutically acceptable salt or stereoisomer thereof. 5. The compound of claim 1, wherein the compound has the following structure (4a): or a pharmaceutically acceptable salt thereof. 6. The compound of claim 1, wherein the compound has the following structure (4b): 15 or a pharmaceutically acceptable salt thereof. 7. The compound of claim 1, wherein the compound has the following structure (4c): or a pharmaceutically acceptable salt thereof. 8. The compound of claim 1, wherein the compound has the following structure (4d): or a pharmaceutically acceptable salt thereof. A compound, or a pharmaceutically acceptable salt thereof, of any one of claims 1 to 8 for use in the modulation of androgen receptor (AR) activity for testing and research purposes. 10. A compound, or a pharmaceutically acceptable salt thereof, of any one of claims 1 to 10 8 for use in the modulation of the androgen receptor (AR) activity, optionally in which the modulation of the androgen receptor (AR) activity serves to treat one or more of the following: prostate cancer , breast cancer, ovarian cancer, endometrial cancer, salivary gland carcinoma, hair loss, acne, hirsutism, ovarian cysts, polycystic ovarian disease, precocious puberty, spinobulbar muscle atrophy and age-related macular degeneration.

eleven.

The compound for the use of claim 10, wherein the indication is prostate cancer.

12.

A pharmaceutical composition comprising a compound of any one of claims 1 to 8 and

a pharmaceutically acceptable vehicle. twenty 13. A pharmaceutical composition comprising a compound of any one of claims 1 to 8, an additional therapeutic agent and a pharmaceutically acceptable carrier, wherein the additional therapeutic agent is for the treatment of prostate cancer, breast cancer, cancer ovarian, endometrial cancer, salivary gland carcinoma, hair loss, acne, hirsutism, ovarian cysts, polycystic ovarian disease, 25 precocious puberty, spinobulbar muscular atrophy or age-related macular degeneration, and in which the additional therapeutic agent is MDV3100, TAK 700, TOK 001; RNA-509; abiraterone acetate, bicalutamide, nilutamide, flutamide, cyproterone acetate, docetaxel, Bevacizumab (Avastin), OSU-HDAC42, VITAXIN, sunitumib, ZD-4054, Cabazitaxel (XRP-6258), MDX-010, Ipilimumab) OGX oil, finasteride, dutasteride, turosteride, bexlosteride, izonsteride, FCE 28260, SKF105,111 or a related compound thereof.

14.

A pharmaceutical composition of any one of claims 12 to 13 for use in the modulation of androgen receptor (AR) activity.

fifteen.

The composition for the use of claim 14, wherein the modulation of the receptor activity of

35 androgens (RA) is for the treatment of one or more of the following: prostate cancer, breast cancer, ovarian cancer, endometrial cancer, salivary gland carcinoma, hair loss, acne, hirsutism, ovarian cysts, Polycystic ovarian disease, precocious puberty, spinobulbar muscular atrophy and age-related macular degeneration.